Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases in the elderly affecting approximately 23% of Americans 60 years of age and older. Estimates of the total economic burden of T2DM exceed $100 billion/year, of which a major proportion can be attributed to persons in this age group. It is well established that insulin resistance plays a major role in the pathogenesis of T2DM associated with aging but the mechanisms responsible for its development remain poorly understood. In this regard recent multinuclear (1H/13C) magnetic resonance spectroscopy (MRS) studies by our group have demonstrated reduced basal mitochondrial function in skeletal muscle associated with increased intramyocellular and hepatic triglyceride content and insulin resistance in healthy, lean, elderly individuals. This led us to hypothesize that reduced mitochondrial function associated with aging leads to reduced fat oxidation predisposing these individuals to increases in intramyocellular and intrahepatic lipid content leading to defects in insulin signaling and insulin resistance. The studies proposed in this grant will build on these novel findings to further explore the potential role of altered muscle mitochondrial function in the pathogenesis of insulin resistance and T2DM in the elderly as well as the potential role of skeletal muscle insulin resistance in predisposing these individuals to increased hepatic de novo lipogenesis resulting in atherogenic dyslipidemia, non alcoholic fatty liver disease (NAFLD), and the metabolic syndrome. Specifically, we will apply state-of-the-art 1H/13C MRS techniques in combination with newly developed liquid chromatography tandem mass spectrometry methods to examine: 1) the impact of aging on insulin-stimulated mitochondrial function, 2) the role of skeletal muscle insulin resistance in the elderly in promoting increased hepatic de novo lipogenesis, 3) the impact of aging on the relative contributions of basal and insulin stimulated muscle mitochondrial glucose and fat oxidation in muscle biopsies, and 4) development and test of novel 13C MRS techniques to non-invasively determine the effects of aging on basal and insulin stimulated relative contributions of muscle mitochondrial glucose and fat oxidation in muscle. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases in older adulthood and estimates of the total economic burden of T2DM exceed $130 billion/year. The studies proposed in this grant will build on our recent observations demonstrating a potential role of altered mitochondrial function in the pathogenesis of insulin resistance and T2DM in the elderly as well as the potential role of skeletal muscle insulin resistance predisposing these individuals to atherogenic dyslipidemia. It is anticipated that the results from these patient-oriented hypothesis-driven studies will provide important new insights into the pathogenesis of insulin resistance and atherogenic dyslipidemia associated with aging and provide new targets to prevent T2DM and promote healthy aging.